US5759535A - Immunotherapeutic strategies for the treatment of cancer - Google Patents

Immunotherapeutic strategies for the treatment of cancer Download PDF

Info

Publication number
US5759535A
US5759535A US08/242,405 US24240594A US5759535A US 5759535 A US5759535 A US 5759535A US 24240594 A US24240594 A US 24240594A US 5759535 A US5759535 A US 5759535A
Authority
US
United States
Prior art keywords
cells
tumor
interleukin
cell
carcinoma
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US08/242,405
Other languages
English (en)
Inventor
Edward P. Cohen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Illinois at Chicago
Original Assignee
Research Corp Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Research Corp Technologies Inc filed Critical Research Corp Technologies Inc
Priority to US08/242,405 priority Critical patent/US5759535A/en
Priority to PCT/US1995/005794 priority patent/WO1995031107A1/fr
Assigned to NATIONAL INSTITUTES OF HEALTH, THE EXTRAMURAL INVENTIONS OFFICE, THE reassignment NATIONAL INSTITUTES OF HEALTH, THE EXTRAMURAL INVENTIONS OFFICE, THE CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: ILLINOIS, UNIVERSITY OF
Assigned to RESEARCH CORPORATION TECHNOLOGIES, INC. reassignment RESEARCH CORPORATION TECHNOLOGIES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: COHEN, EDWARD P.
Application granted granted Critical
Publication of US5759535A publication Critical patent/US5759535A/en
Assigned to UNIVERSITY OF ILLINOIS AT CHICAGO reassignment UNIVERSITY OF ILLINOIS AT CHICAGO ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RESEARCH CORPORATION TECHNOLOGIES, INC.
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • TAA tumor-associated antigens
  • TAA tumor-associated antigens
  • oncogene products activated by mutation and rearrangement e.g., position 12 mutation in p21 ras , P210 product of bcr/abl rearrangement
  • mutated tumor-suppressor gene products e.g., p53
  • reactivated embryonic gene products not expressed in adult tissues e.g., P91A found in the P815 mastocytoma
  • MAGE 1 found in melanomas and human breast tumors
  • tissue specific self-antigens expressed by tumors e.g., tyrosinase
  • tumor cell populations express certain common TAAs, but are heterogeneous with respect to the spectrum of TAAs that they express. It is possible that the complete spectrum of tumor associated T-cell epitopes in a given tumor may eventually be identified. However, despite the array of tumor-associated T-cell epitopes expressed in tumors, tumor cells remain poorly immunogenic.
  • cytokine genes have been introduced into tumor cells to produce vaccines having varying degrees of effect on both tumorigenicity and immunogenicity.
  • tumor cells have been modified with genes for interleukin-2 (IL-2)(Porgador, A., et al., Int. J. Cancer 53:471-477 1993!); interferon- ⁇ , (IFN- ⁇ )(Porgador, A., et al., Int. Immunol 150:1458-1570 1993!); granulocyte-macrophage colony stimulating factor (GM-CSF) (Dranoff, G., et al., Proc. Nat. Acad. Sci. USA 90:3539-3543 1993! and several others.
  • IL-2 interleukin-2
  • IFN- ⁇ interferon- ⁇
  • GM-CSF granulocyte-macrophage colony stimulating factor
  • MHC class I antigens Following exposure of cells to cytokines or transfection of cells with genes specifying MHC class I antigens have been shown to render the treated cells more susceptible to lysis by CTLs. (Weber, J. S., et al., Cancer Res. 48:5818 1988!); Zoller, M. Int. J. Cancer 41:256 1988!); Porgador, A., et al., J. Immunogenet. 16:291 1989!).
  • Kim, T. S. et al. have shown that when certain specific tumor antigens are expressed in allogeneic cells, that the cells stimulate an improved T-cell response to the specific antigens expressed by the allogeneic cells. (Int. J. Cancer 55:865-872 1993!; and Kim, T. S. et al., Int J. Cancer 51:283-289 1992!).
  • the system described by Kim et al. involved the selection of a subset of cells expressing a very limited array of tumor-associated antigens.
  • the use of this subset of cells as a vaccine suffers from the disadvantage that they express only a small proportion of the total array of tumor-antigens that may be expressed in any given tumor. Thus, it is likely that the immune system will recognize only the antigens expressed by the vaccine and thereby select for the survival of those tumor cells expressing other antigens.
  • the present invention is directed to a method for the treatment of neoplastic disease comprising administering to a mammal having a tumor a cellular immunogen comprising an allogeneic population of cells expressing one or more cytokines and tumor associated antigens encoded by autologous genomic tumor DNA.
  • the invention is also directed to the above-described method wherein the one or more cytokines is capable of augmenting a T-cell response.
  • the cytokine is selected from the group consisting of interferon ⁇ , interferon- ⁇ , the interleukins 1-12, tumor necrosis factor, granulocyte macrophage colony stimulating factor, granulocyte colony stimulating factor and other cytokines capable of augmenting a T-cell response.
  • the allogeneic cell population may express endogenous cytokine genes or they may be genetically modified to express the one or more cytokine.
  • Tumors comprehended by the method of the present invention include but are not limited to melanoma, lymphoma, plasmocytoma, sarcoma, leukemia, carcinomas, such as renal cell carcinoma, lung carcinoma, breast carcinoma, colon carcinoma, prostate carcinoma and others.
  • the method of the present invention is applicable to the treatment of neoplastic disease in humans and in non-human mammals.
  • the invention is also directed to a cellular immunogen comprising an allogeneic population of cells expressing one or more cytokine, and tumor-associated antigens encoded by autologous genomic tumor DNA.
  • Another aspect of the invention is a cellular immunogen produced by the process of providing an allogeneic population of cells which expresses a cytokine encoded by an endogenous cytokine gene or which is encoded by a foreign cytokine gene introduced into the allogeneic cells; introducing into the allogeneic cells genomic DNA derived from a portion of a tumor to be treated whereby at least a portion of allogeneic cells express, one or more tumor associated antigens encoded by the tumor DNA.
  • Still another aspect of the invention is a pharmaceutical composition useful in the treatment of neoplastic disease comprising the cellular immunogen of the present invention and a pharmaceutically acceptable carrier, diluent or adjuvant.
  • the invention is also directed to a medicament useful in a method for treating neoplastic disease, the medicament comprising the cellular immunogens of the present invention.
  • FIG. 1 is a graph showing the survival curves for mice bearing B16F1 melanoma treated with irradiated B16F1 cells (solid squares), LM-IL-2/Hyg (solid triangles), LM-IL-2/MOPC-315 (open circles), LM-IL-2/B16F10 (open squares), and LM-IL-2/B16F1 (open triangles), or untreated mice (solid circles).
  • FIG. 2A is a graph showing the survival curves for mice bearing B16F1 melanoma treated with LM-IL-2 cells (solid squares), LM-IL-2/C1498 cells (solid triangles), LM-IL-2/J558 cells (open circles), LM-IL-2/B16F1 cells (open squares), or untreated mice (solid circles).
  • FIG. 2B is a graph showing the survival curves for mice bearing C1498 lymphoma treated with LM-IL-2/B16F1 cells (solid squares), LM-IL-2/C1498 cells (solid triangles), and untreated mice (solid circles).
  • the present invention is directed to an immunotherapeutic strategy for the treatment of neoplastic disease and to materials useful in implementing that strategy.
  • the strategy is based on the likelihood that several if not many genes specifying tumor-associated antigens (TAA) have undergone rearrangement in tumor cells and/or on populations of cells comprising a tumor. Further, allogeneic cells of when transfected with genomic DNA derived from a portion of tumor to be treated or from another similar tumor, will result in a population of cells at least some of which will express one or more of the TAAs in the context of the MHC.
  • TAA tumor-associated antigens
  • TAAs in the context of the MHC thus allows the presentation of T-cell specific epitopes in such a way as to provoke or augment a cytotoxic T-cell response to the TAAs.
  • the strategy is further based on the ability of cytokines such as interleukin-2 (IL-2), when produced by the transfected cells to further augment the T-cell response by causing an expansion of the T-cell population that recognizes the tumor-associated T-cell epitopes expressed on the transfected cells.
  • IL-2 interleukin-2
  • tumors were not observed in immunocompetent mice injected with non irradiated IL-2-secreting or non-secreting cells that expressed allogeneic determinants. Like other allografts, the cells were eventually rejected by the immunocompetent recipients. Furthermore, allogeneic antigens expressed by cells chosen to receive the tumor DNA acted synergistically with the TAA in generating the cellular anti-tumor response.
  • cytotoxic T-lymphocytes CTLs
  • the immunogenic properties of tumor cells transfected with genes specifying allogeneic determinants supports this explanation (Hui, K. M., et al., J. Immunol. 143:3835-3843,(1989); and Ostrand-Rosenberg, et al. Int. J. Cancer , 6(Suppl.): 61-68 (1991).
  • the second is that allogeneic MHC class I determinants present tumor associated T-cell epitopes directly to CTL precursors.
  • the high, local environment of IL-2, secreted by the genetically modified cells, further augments the generation of large numbers of CTLs with anti-tumor specificity.
  • Lyt-2.2 + (CD8 + ) anti-tumor CTLs were predominant in mice immunized with cells transfected with genomic DNA from the tumor cells.
  • natural killer/lympholine activated killer cells (NK/LAK) cells were the predominant anti-tumor cell-type in mice immunized with cells transfected with DNA from MOPC-315 cells, or cells modified for IL-2-secretion alone. It is likely that the activation of NK/LAK cells reflected the secretion of IL-2 by the modified cells.
  • Lyt-2.2 + cells were the predominant anti-tumor cell-type in C57BL/6 mice immunized with non-IL-2-secreting LM cells that were selected for the expression of TAA, and that NK/LAK cells were predominant in mice injected with TAA-non expressing cells modified to secrete IL-2alone.
  • LM-IL-2 cells transfected with genomic DNA from the tumor cells may have been responsible for the activation of anti-tumor Lyt-2.2 + T-lymphocytes (CD8 + ).
  • the plasmid pZipNeoSVIL-2containing the gene for interleukin-2 (IL-2) along with a neo 4 gene (which confers resistance to G418) was introduced into LM cells, a mouse fibroblast cell line of C3H origin expressing defined MHC class I antigens (H-2 k ). After initial selection in growth medium containing G418, IL-2-secretion was confirmed and the cells were then co-transfected with genomic DNA from B16F1 or B16F10 melanoma cells along with DNA from a plasmid (pHyg) that confers resistance to hygromycin.
  • IL-2 interleukin-2
  • H-2 k mouse fibroblast cell line of C3H origin expressing defined MHC class I antigens
  • mice with melanoma treated with IL-2-secreting LM cells transfected with genomic DNA from MOPC-315 cells, a non-immunologically cross-reactive murine tumor As determined by the capacity of monoclonal antibodies to T cell-subsets to inhibit the anti-melanoma response in a .sup. ⁇ 1 Cr-release assay, the anti-melanoma immunity in mice immunized with cells transfected with genomic DNA from either B16F1 or B16F10 cells was mediated primarily by Lyt-2.2 + (CD8 + ) T-cells.
  • cellular immunogens may be prepared by transfecting allogeneic cells modified to express a cytokine capable of augmenting a T-cell response with genomic DNA taken from a portion of tumor or tumor cells derived directly from a patient. The patient may then be treated with the cellular immunogen to induce tumor regression.
  • IL-2-secreting LM cells were prepared by transfecting the IL-2gene into the cells using the vector pZipNeoSVIL-2(Yamada, et al., EMBO J. 6:2705-2709 (1987)) using cationic liposomes (Felgner, et al., Proc. Natl. Acad. Sci. USA 84:7413-7417 (1987)).
  • the plasmid vector comprises the human IL-2gene and the neo r gene, both under control of the Moloney leukemia virus long terminal repeat.
  • the neo r gene confers resistance to the aminoglycoside antibiotic, G418 (Colbere-Garapin, et al., J. Mol.
  • the gene may also be transduced into cells via virus particles, by transfecting pZipNeoSVIL-2into a viral replication-defective packaging cell line. (Markowitz, et al., Virol 167:400-406(1988)).
  • LM cells were transfected with the plasmid pZipNeoSV(X).
  • pZipNeoSV(X) comprises the Neo r gene under the transcriptional control of the Maloney leukemia virus long terminal repeat, but lacks the gene for IL-2.
  • This plasmid may also be packaged in a viral replication-defective packaging cell line.
  • Transfected cells were maintained for 14 days in growth medium containing 1 mg/ml G418 (G418-growth medium).
  • G418-growth medium 1 mg/ml G418
  • LM-IL-2-secreting LM cells LM-IL-22 were routinely passaged in growth medium containing 300 mg/ml G418 to eliminate cells that had lost the Neo r gene (and, by inference, the IL-2gene).
  • IL-2-secretion by the G418 -resistant cells was assayed using the IL-2-dependent cell-line, CTLL-2 as described in Gillis, et al., J. Immunol. 120:2027-2032 (1978).
  • IL-2-dependent CTLL-2 cells were maintained in RPMI-1640 medium supplemented with 10% FBS, 2 mM glutamine, 0.5 mM sodium pyruvate, 15 mM HEPES, 5 ⁇ 10 -2 mM 2-mercaptoethanol and 100 units/ml IL-2(Genzyme, Cambridge, Mass.).
  • One unit of IL-2gave half-maximal proliferation of CTLL-2 cells under these conditions are shown in Table 1.
  • Table 1 The values shown in Table 1 represent the mean from three different experiments. The results show that 1 ⁇ 10 6 LM-IL-2 cells produce about 10,000 units/10 6 cells when assayed over 48 hours and that IL-2expression in these cells was stable even after 6 months of continuous culture. Further, cells transfected with pZipNeoSV(x) produced no detectable IL-2.
  • RT-PCR Reverse Transcription-Polymerase Chain Reaction
  • RT-PCR was used as a further test of the expression of the IL-2-gene by LM-IL-2 cells.
  • Total cellular RNA was prepared from LM-IL-2cells and from LM cells transfected with pZipNeoSV(X) according to the method described by Chomczynski and Sacchi (Chomczynski, et al., Anal. Biochem. 162:156-159 (1987)).
  • RNA samples were transcribed into cDNA in a reverse transcription reaction mixture containing 50 mM Tris-HCl (pH 8.3), 75 mM KC1, 3 mM MgCl 2 , 10 mM dithiothreitol, 0.5 mM each of deoxynucleotide triphosphate (dATP, dTTP, dGTP, and dCTP), 1 unit/ml RNase inhibitor, 2.5 units/ul Moloney murine leukemia virus reverse transcriptase (MMLV-RT) (Gibco BRL, Grand Island, N.Y.) and 0.03 ⁇ g/ml oligo-deoxythymidylateprimer (Gibco BRL).
  • MMLV-RT Moloney murine leukemia virus reverse transcriptase
  • RT-PCR amplification of cDNA was performed in a reaction mixture consisting of 0.4 mM of each specific primer for the IL-2 or the Neo r gene (Clontech Lab., Palo Alto, Calif.), 3-5 ⁇ l of the cDNA sample, 1.5 mM MgCl 2 , and 2.0 U Taq polymerase (Gibco BRL).
  • the Neo specific primers were:
  • Amplification was carried-out for 38 cycles of 94° C. (1 min), 55° C. (1 min), 72° C. (1 min) for the Neo cDNA amplification.
  • IL-2 specific primers used for the detection of IL-2 specific transcripts were;
  • Amplification of the IL-2 cDNA was carried out for 32 cycles of 94° C. (45 sec), 60° C. (45 sec), 72° C. (2 min) using a Perkin-Elmer Cetus thermal-cycler.
  • Genomic DNA from LM-IL-2 cells was prepared as described by Wigler, et al., Cell 14:725-731(1978). Southern blot analysis was performed using this DNA to confirm the integration of the IL-2-gene into the transfected cell genome, as described previously (Russell, et al., Int. J. Cancer 47:244-251(1991); and Sambrook, et al., Molecular Cloning; A Laboratory Manual, Cold Spring Harbor Laboratory, N.Y. (1992)). 32 P-labeled cDNA encoding human IL-2derived from pZipNeoSVIL-2was used as a probe.
  • the probe was labeled using methods described in Sambrook, et al., Molecular Cloning; A Laboratory Manual, Cold Spring Harbor Laboratory, N.Y. (1992). This analysis revealed that two copies of the IL-2gene were integrated into the DNAs of the transfected cells
  • the plasmid pHyg carries an E. coli gene encoding a hygromycin B phosphotransferase (Sugden, et al., Mol. Cell. Biol. 5:410 (1985)).
  • a hygromycin B phosphotransferase As an additional control, other LM-IL-2 cells were transfected with DNA (1 ⁇ g) from pHyg alone.
  • Other selectable markers such as the herpes simplex thymidine kinase gene may be used to co-transfect with genomic DNA. The choice of a selectable marker will depend on the specific cell line to be transfected and may be readily determined by those of ordinary skill in the art. After transfection the cells were maintained for 14 days in growth medium containing 400 ⁇ g/ml hygromycin.
  • LM-IL-2-secreting LM cells (LM-IL-2) transfected with genomic DNA from B16F1 (LM-IL-2/B16F1), 2 /B16F10 (LM-IL2/B16F10), or MOPC-315 (LM-IL-2/MOPC-315 ) cells, secreted approximately the same amount of IL-2as LM-IL-2 cells when tested using the method described in Example 1.
  • B16F1 (H-2 b ) is a highly malignant cell-line derived from a melanoma occurring spontaneously in a C57BL/6 mouse (H-2 b ).
  • the B16F1 cell line is available from the American Type Culture Collection, Rockville, Md. under ATCC accession no. 6323.
  • B16F10 is a derivative of B16F10 selected for its metastatic properties. Both cell-lines, were maintained by serial passage in histocompatible C57BL/6 mice (Jackson Labs., Bar Harbor, Me.) or at 37° C.
  • MOPC-315 cells H-2 d
  • H-2 d a mineral oil-induced plasmacytoma of BALB/c mouse origin (H-2 d ) (ATCC accession no. TIV23) were maintained by serial passage in BALB/c mice.
  • LM cells H-2 k were obtained from the American Type Culture Collection, Rockville, Md. (ATCC accession no. CCL1-3). The cell-lines were maintained at 37° C. in a humidified 7% CO 2 /air atmosphere in growth medium.
  • mice were injected subcutaneously (sc) with 5 ⁇ 10 3 viable B16F1 cells.
  • the mice received the first of three injections at weekly intervals of 4 ⁇ 10 6 LM-IL-2/B16F1 cells or LM-IL-2/B16F10 cells in a volume of 0.1-0.3 ml in growth medium.
  • Other mice with melanoma were treated with equal numbers of LMIL-2/MOPC-315 with LM-IL-2 cells transfected with DNA from pHyg alone (LM-IL-2/Hyg), with irradiated melanoma cells irradiated with 5000 rads of radiation from a 60 Co source or the mice were not injected.
  • the tumor was less than 2 mm in diameter. Life table methods and log rank analyses were used to determine the statistical differences between the proportion of mice surviving following the different treatments.
  • mice with melanoma treated with LM-IL-2/B16F1 cells had a median survival time (MST) of 55.0 days while those treated with LM-IL-2/B16F10 cells had an MST of 46.4 days.
  • MSTs for both treated groups were significantly longer (P ⁇ 0.05) than mice with melanoma treated with cells from any of the various control groups.
  • the median survival of untreated mice injected with B16F1 cells alone was 26 days. Treatment with irradiated B16F1 cells failed to prolong the survival of mice with melanoma.
  • mice with melanoma were not significant.
  • a cellular immunogen expressing IL-2and IFN.sub. ⁇ along with tumor antigens also increased the MST in melanoma bearing mice.
  • Neoplasms were not detected in tumor-free mice injected with viable IL-2-secreting transfected LM cells. Like other allografts, the cells were rejected over a period of two to three weeks.
  • C57BL/6 mice (at least 2 per group) were injected subcutaneously (s.c.) and intraperitoneally (i.p.) respectively with 2 ⁇ 10 LM-IL-2/B16F1 or LM-IL-2/B16F10 cells at each injection site.
  • spleen cell suspensions were prepared by forcing the mouse spleens through 40 gauge stainless steel screens in 5 ml of growth medium and transferred to 15 ml centrifuge tubes (Sarstedt, Newton, N.C.). Large clumps of cells and debris were allowed to settle for 1 min and the cells remaining in the supernatant were collected, overlaid onto a Ficoll/Hypaque gradient (Pharmacia, Piscataway, N.J.) and centrifuged (2,000 rpm) for 25 min at room temperature. The viability of the mononuclear cells at this point was greater than 98%, as determined by trypan blue dye exclusion (0.4% trypan blue).
  • Spleen cell-mediated cytotoxicity measurements against B16 cells were performed in a standard 51 Cr-release assay. Briefly, 5 ⁇ 10 B16F1 cells were labeled with 51 Cr during a 1 hr incubation at 37° C. in growth medium containing 100 mCi of sodium 31 Cr (Amersham, Arlington Heights, Ill.). After three washes with Dulbecco's modified Eagle's medium, 1 ⁇ 10 4 51 Cr-labeled B16 cells were incubated for 4 hrs at 37° C. with the nonplastic-adherent population of spleen cells from the immunized mice (prepared as described above), at effector cell:target cell ratios (E:T) of 100:1 and 200:1. Afterwards, the percent specific cytolysis was calculated as: ##EQU1##
  • mice immunized with LM-IL-2/B16F1 cells were significantly (p ⁇ 0.001) higher in spleen cell-populations from mice immunized with LM-IL-2/B16F1 cells and from mice immunized with LM-IL-2/B16F10 than in spleen cell populations from non-immunized mice.
  • An anti-melanoma response was also detected in mononuclear cell-populations from the spleens of mice immunized with IL-2-secreting LM cells transfected with genomic DNA from MOPC-315 cells, and in a population of cells from mice immunized with IL-2-secreting LM cells transfected with DNA from the plasmid pHyg alone.
  • the magnitude of these responses was clearly less than that present in mice immunized with LM-IL-2/B16F1 or LM-IL-2/B16F10 cells.
  • mice susceptible to the growth of melanoma with an unfractionated population of IL-2-secreting cells transfected with genomic DNA from either of two melanoma cell-lines induced specific anti-melanoma immune responses that were capable of prolonging the survival of mice with melanoma.
  • the immunity was mediated primarily by Lyt-2.2 + T cells and, to a lesser extent, NK/LAK cells.
  • mice bearing either C1498 lymphoma or B16 melanoma were tested for their effects on the median survival time of mice bearing either C1498 lymphoma or B16 melanoma.
  • the cellular immunogens were produced by transfecting LM-IL-2 cells produced as described in Example 1, C1498 lymphoma cells (ATCC Accession No. TIV49), or J558 myeloma cells (ATCC Accession No. TIV6) using the method described in Example 2.
  • the cellular immunogens produced were designated LM IL-2/C1409 and LM IL-2/J558 (expressing IL-2 and J558 tumor-associated antigens).
  • the LM IL-2/B16F cellular immunogens produced in Example 2 were used in these studies.
  • mice C57BL/6 mice (5 per group) were subcutaneously injected with 5 ⁇ 10 3 melanoma cells or with 1 ⁇ 10 5 C1498 cells. At the same time, mice receiving tumor cells also received the first of three weekly subcutaneous injections of 4 ⁇ 10 6 cells of one of the cellular immunogens shown in Table 3.
  • Animals receiving B16 melanoma cells were treated with LM IL-2/B16, LIL-2/C 1498, LM IL-2/J558, or LM IL-2 cellular immunogens. Control animals with B16 melanoma received no treatment. Animals receiving C1498 lymphoma cells were treated with LM IL-2/B16 or LM IL-2/C1498 cells. Control animals with C1498 lymphoma received no treatment.
  • control mice receiving B16 melanoma cells or C1498 lymphoma cells with no treatment had a medium survival time of 21.6 ⁇ 3.7 days and 20.6 ⁇ 0.49 days respectively.
  • LM IL-2/B16 constructs extended the median survival time the most in animals with B16 melanoma while LM IL-2/C1498 increased the median survival time the most in animals with C1498 lymphoma.
  • significant increases in median survival time were seen in all animals receiving any allogeneic cell constructs including the LM IL-2 construct which had not been transfected with genomic DNA from any tumor.
  • the 51 Cr-release assay described in Example 6 was used to detect spleen-cell mediated immunity (cytotoxicity) toward B16 melanoma and C1498 lymphoma.
  • mice Tumors were established in naive C57BL/6 mice by subcutaneously injecting either 5 ⁇ 10 3 B16 melanoma cells or 1 ⁇ 10 5 C1498 lymphoma cells.
  • the mice receiving the B16 melanoma cells were each treated with 4 ⁇ 10 6 LM IL-2/B16, LM IL-2/C1498, LM IL-2/J558, LM IL-2cells simultaneously with the administration of the cellular immunogens followed by two more treatments with the cellular immunogens at 7 day intervals.
  • One group of control mice receiving B16 cells were left untreated.
  • mice receiving C1498 lymphoma cells were each treated with 4 ⁇ 10 6 LM IL-2/B16 or with LM IL-2/C1498 cells as described in Example 5.
  • One group of control mice receiving C1498 cells were left untreated. Seven days after the last injection, mononuclear cells were obtained from the spleens of mice in each group as described in Example 6. Spleen cells were then incubated for 7 days with mitomycin-C treated cellular immunogens of the same cell type used for immunization. The spleen cells were then tested for their capacity to lyse 51 Cr-labeled B16 melanoma cells, or C1498 lymphoma cells as described in Example 6.
  • NK/LAK cells The involvement of NK/LAK cells in the cell mediated response was also tested by adding an excess of monoclonal antibodies specific for NK/LAK cells to the spleen-cell suspension prior to their use in the 5 1 Cr-release assay. The results of these assays are shown in Table 4.
  • cytolysis of tumor cells was greatest toward a given tumor when the cellular immunogen used for immunization had been transfected with autologous tumor DNA.
  • significant cytolysis was also seen using spleen cells from animals receiving cellular immunogens that had been transfected with heterologous tumor DNA although it was significantly lower than with cells containing autologous tumor DNA.
  • individualized cellular immunogens directed to a specific tumor which will extend the median survival time of patients with that specific tumor.
  • Such individualized cellular immunogens will be useful either alone or in combination with other treatment modalities for the treatment of neoplastic disease. This approach will be useful in treating not only melanoma but also most if not all other tumor types including but not limited to lymphomas, sarcomas, carcinomas, plasmocytomas, leukemias, and tumors of nervous system origins.
  • the preparation of individualized cellular immunogens entails preparing a modified allogeneic cell line having a MHC type (or HLA type) which is foreign to the patient.
  • a cell type is exemplified above by LM cells (H-2 k ).
  • LM cells H-2 k
  • Exemplary human cell lines whose HLA type has already been determined include human melanoma cell lines available from the ATCC under accession numbers HTB70, HTB63 and HTB71.
  • Exemplary modifications include the introduction of a vector containing an expressible cDNA encoding a cytoline such as IL-2, INF-.sub. ⁇ , granulocyte-colony stimulating factor (Colombo, M.P. et al., J. Exp. Med. 173: 889-847 1991!); interferon ⁇ (IFN ⁇ ) (Ferrantini, M., et al. Cancer Res. 53: 1107-1112 1993!); interleukin-6 (IL-6) (Porgador, et al., Cancer Res. 52: 3679-3686 1992!); tumor necrosis factor (TNF) (Blankenstein, et al. J. Exp. Med.
  • IL-2 interferon ⁇
  • IFN ⁇ interferon ⁇
  • IL-6 interleukin-6
  • TNF tumor necrosis factor
  • cytokines capable of augmenting an anti-tumor response to a tumor antigen.
  • a vector is exemplified by pZipNeoSVIL-2in Example 2 described above.
  • allogeneic cells lines expressing endogenous cytokines may also be used.
  • a modified allogeneic cell line is established and is shown to produce the cytokine or cytokines of interest (the combination of IL-2and INF-.sub. ⁇ is preferred), then this cell line is used as a target for further modification by introducing isolated purified genomic DNA taken from a patient's own tumor. Tumor samples are obtained during surgery, by needle aspiration, or by other well-known methods. Genomic DNA is then isolated and purified from the tumor sample directly using methods well known in the art including those set out in Sambrook, et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory N.Y. (1992). Tumor samples may also be grown in culture using methods well known in the art in order to increase the amount of DNA available for transfection or to select for a particular sub-population of tumor cells from which to isolate DNA.
  • Isolated purified DNA from the tumor or tumor cells is then transfected into a population of the modified allogeneic cells along with a selectable marker such as pHyg or any of a number of other selectable markers.
  • Genomic DNA may be transfected into the modified allogeneic cells using any of a number of methods including the use of cationic liposomes as described in Example 4, by calcium-phosphate co-precipitation, by electroporation or by any of a number of other well known methods for introducing genomic DNA into cells.
  • Transfected cells are then grown under selection pressure to kill 100% of the cells that fail to express the selectable marker. Those cells surviving selection are then pooled to provide a tumor-associated antigens which will serve to stimulate a T-cell mediated immune response.
  • T-cell responses have been shown to increase the MST of animals bearing autologous tumors.
  • a preferred dosage range is from about 1 ⁇ 10 3 to about 5 ⁇ 10 9 cells per injection.
  • the cellular immunogen may administered as a live vaccine or the immunogen may be modified by irradiation, chemical treatment or other means known in the art so as to render the cellular immunogen incapable of proliferation.
  • the subcutaneous route of injection is preferred but other routes such as the intraperitoneal, intramuscular, or intravenous routes are contemplated by the present invention.
  • the present invention also permits the preparation of generic cellular immunogens which express one or more cytokines and which express tumor associated antigens encoded by genomic DNA derived from tumors or tumor cells other than the patients own tumor. These generic cellular immunogens are prepared as described above.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Zoology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Microbiology (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Toxicology (AREA)
  • Mycology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oncology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US08/242,405 1994-05-13 1994-05-13 Immunotherapeutic strategies for the treatment of cancer Expired - Lifetime US5759535A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US08/242,405 US5759535A (en) 1994-05-13 1994-05-13 Immunotherapeutic strategies for the treatment of cancer
PCT/US1995/005794 WO1995031107A1 (fr) 1994-05-13 1995-05-11 Strategies immunotherapeutiques appliquees dans le traitement du cancer

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US08/242,405 US5759535A (en) 1994-05-13 1994-05-13 Immunotherapeutic strategies for the treatment of cancer

Publications (1)

Publication Number Publication Date
US5759535A true US5759535A (en) 1998-06-02

Family

ID=22914666

Family Applications (1)

Application Number Title Priority Date Filing Date
US08/242,405 Expired - Lifetime US5759535A (en) 1994-05-13 1994-05-13 Immunotherapeutic strategies for the treatment of cancer

Country Status (2)

Country Link
US (1) US5759535A (fr)
WO (1) WO1995031107A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999006544A1 (fr) * 1997-07-29 1999-02-11 The Immune Response Corporation Compositions a base de cytokine membranaire et procedes de modulation d'une reponse immune faisant appel a ces compositions
WO1999047178A1 (fr) * 1998-03-20 1999-09-23 Genzyme Corporation Nouvelles paires complementaires de recepteurs /ligands et immunotherapie adoptive les utilisant
US6277368B1 (en) 1996-07-25 2001-08-21 The Regents Of The University Of California Cancer immunotherapy using autologous tumor cells combined with cells expressing a membrane cytokine
US20030170656A1 (en) * 1995-10-16 2003-09-11 Chiron Corporation Method of screening for factors that modulate gene expression
US20060009393A1 (en) * 1999-10-02 2006-01-12 The Government of the U.S.A as represented by the Secretary of the Dept. of Health & Human Services Immunogenic epitopes for fibroblast growth factors 5 (FGF-5)
EP1871166A2 (fr) * 2005-03-29 2008-01-02 The Board Of Trustees Of The University Of Illinois Vaccins contre le cancer et methodes therapeutiques
EP1964573A2 (fr) 1999-10-22 2008-09-03 Aventis Pasteur Limited Procédé d'induction et/ou amélioration d'une réponse immune vers des antigènes de tumeurs
US20080305131A1 (en) * 1997-01-31 2008-12-11 The Board Of Trustees Of The University Of Illinois Cancer Immunotherapy with Semi-Allogeneic Cells
US20110014241A1 (en) * 2008-03-14 2011-01-20 The Board of Trustees of the Unversity Illinois Therapeutic Cancer Antigens
US11471453B2 (en) * 2013-11-26 2022-10-18 Technion Research & Development Foundation Limited Neuronal modulation

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6207147B1 (en) 1996-10-11 2001-03-27 The Regents Of The University Of California Cancer immunotherapy using tumor cells combined with mixed lymphocytes
EP0815204B1 (fr) * 1995-03-17 2006-09-06 The Regents Of The University Of California Methode de traitement de tumeurs a l'aide de lymphocytes humains alloactives
US7361332B2 (en) 1995-03-17 2008-04-22 The Regents Of The University Of California Treating tumors using implants comprising combinations of allogeneic cells
US6033674A (en) * 1995-12-28 2000-03-07 Johns Hopkins University School Of Medicine Method of treating cancer with a tumor cell line having modified cytokine expression
JP2001517206A (ja) * 1996-08-16 2001-10-02 ザ ジョンズ ホプキンズ ユニヴァーシティ スクール オヴ メディシン 免疫優性な共有黒色腫抗原を発現する黒色腫細胞株およびその使用方法
GB9620350D0 (en) 1996-09-30 1996-11-13 Maudsley David J Cancer vaccine
US6087174A (en) * 1996-12-26 2000-07-11 Johns Hopkins University, School Of Medicine Growth medium for primary pancreatic tumor cell culture
DE19746173A1 (de) * 1997-10-18 1999-04-22 Boehringer Ingelheim Int Tumorvakzine
DE19821925A1 (de) * 1998-05-15 1999-11-18 Roehnisch Tim Verfahren zur Herstellung einer Zusammensetzung zur Induktion einer tumorspezifischen Immunantwort, sowie Verwendung der Zusammensetzung zur Behandlung von Neoplasien
WO2000004927A1 (fr) * 1998-07-24 2000-02-03 Alleghney University Of The Health Sciences Immunogenes cellulaires allogeniques utiles comme vaccins contre le cancer
CA2424004A1 (fr) * 2000-09-26 2002-04-04 Roger William Hospital Vaccins b.c.g. de recombinaison aux fins du traitement et de la prevention du cancer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993007906A1 (fr) * 1991-10-25 1993-04-29 San Diego Regional Cancer Center Therapie du cancer par le gene de la lymphokine
US5674486A (en) * 1991-06-25 1997-10-07 San Diego Regional Cancer Center Cancer immunotherapy with carrier cells

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5674486A (en) * 1991-06-25 1997-10-07 San Diego Regional Cancer Center Cancer immunotherapy with carrier cells
WO1993007906A1 (fr) * 1991-10-25 1993-04-29 San Diego Regional Cancer Center Therapie du cancer par le gene de la lymphokine

Non-Patent Citations (58)

* Cited by examiner, † Cited by third party
Title
Blankenstein, T. et al., Tumor Suppression after Tumor Cell targeted Tumor Necrosis Factor Gene Transfer, J. Exp. Med., 173: 1047 1052 (1991). *
Blankenstein, T. et al., Tumor Suppression after Tumor Cell-targeted Tumor Necrosis Factor α Gene Transfer, J. Exp. Med.,173: 1047-1052 (1991).
Calver et al., TIG, 10(5): 174 179, 1994. *
Calver et al., TIG, 10(5): 174-179, 1994.
Colombu, M. et al., Granulocyte Colony stimulating Factor Gene Transfer Suppresses Tumorigenicity of a Murine Adenocarcinoma In Vivo, J. Exp. Med., 173: 889 897 (1991). *
Colombu, M. et al., Granulocyte Colony-stimulating Factor Gene Transfer Suppresses Tumorigenicity of a Murine Adenocarcinoma In Vivo, J. Exp. Med., 173: 889-897 (1991).
Dranoff, G. et al., Vaccination with irradiated tumor cells engineered to secrete murine granulocyte macrophage colony stimulating factor stimulates potent, specific, and long lasting anti tumor immunity, Proc. Natl. Acad. Sci. USA, 90: 3539 3543 (1993). *
Dranoff, G. et al., Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity, Proc. Natl. Acad. Sci. USA, 90: 3539-3543 (1993).
Fearon, E.R. et al., Interleukin 2 Production by Tumor Cells Bypasses T Helper Function in the Generation of an Antitumor Response, Cell, 60: 397 403 (1990). *
Fearon, E.R. et al., Interleukin-2 Production by Tumor Cells Bypasses T Helper Function in the Generation of an Antitumor Response, Cell, 60: 397-403 (1990).
Ferrantini, M. et al., l Interferon Gene Transfer into Metastatic Friend Leukemia Cells Abrogated Tumorigenicity in Immunocompetent Mice: Antitumor Therapy by Means of Interferon producing Cells, Cancer Res., 53: 1107 1112 (1993). *
Ferrantini, M. et al., αl-Interferon Gene Transfer into Metastatic Friend Leukemia Cells Abrogated Tumorigenicity in Immunocompetent Mice: Antitumor Therapy by Means of Interferon-producing Cells, Cancer Res., 53: 1107-1112 (1993).
Golumbek, P. et al., Treatment of Established Renal Cancer by Tumor Cells Engineered to Secrete Interleukin 4, Science, 254: 713 716 (1991). *
Golumbek, P. et al., Treatment of Established Renal Cancer by Tumor Cells Engineered to Secrete Interleukin-4, Science, 254: 713-716 (1991).
Hodgson, Exp. Opin. Ther. Pat., 5(5):459 468, 1995. *
Hodgson, Exp. Opin. Ther. Pat., 5(5):459-468, 1995.
Hui, K.M. et al., Tumor rejection mediated by transfection with allogeneic class I histocompatibility gene, J. Immunol., 143: 3825 3843 (1989). *
Hui, K.M. et al., Tumor rejection mediated by transfection with allogeneic class I histocompatibility gene, J. Immunol., 143: 3825-3843 (1989).
Karp, S.E. et al., Cytokine Secretion by Genetically Modified Nonimmunogenic Murine Fibrosarcoma, J. Immunol., 150: 896 908 (1993). *
Karp, S.E. et al., Cytokine Secretion by Genetically Modified Nonimmunogenic Murine Fibrosarcoma, J. Immunol., 150: 896-908 (1993).
Kim, T.S. et al., Immunization with interleukin 2 secreting allogeneic mouse fibroblasts expressiing melanoma assoicated antigens prolongs the survival of tumor bearing mice, Int. J. Cancer, 55: 865 872 (1993). *
Kim, T.S. et al., Immunization with interleukin-2-secreting allogeneic mouse fibroblasts expressiing melanoma assoicated antigens prolongs the survival of tumor-bearing mice, Int. J. Cancer, 55: 865-872 (1993).
Kim, T.S. et al., Independent pathways are involved in the induction of antimelanoma responses in C57BL/6 mice immunized with interleukin 2 secreting allogeneic mouse fibroblasts expressing melanoma associated antigens, J. Immunother., 14: 298 304 (1993). *
Kim, T.S. et al., Independent pathways are involved in the induction of antimelanoma responses in C57BL/6 mice immunized with interleukin-2-secreting allogeneic mouse fibroblasts expressing melanoma associated antigens, J. Immunother., 14: 298-304 (1993).
Kim, T.S. et al., MHC antigen expression by melanomas recovered from mice treated with allogeneic mouse fibroblasts genetically modified for interleukin 2 secretion and the expression of melanoma associated antigens, Cancer Immunol. Immunother., 38: 185 193 (1994). *
Kim, T.S. et al., MHC antigen expression by melanomas recovered from mice treated with allogeneic mouse fibroblasts genetically modified for interleukin-2 secretion and the expression of melanoma-associated antigens, Cancer Immunol. Immunother., 38: 185-193 (1994).
Kim. T.S. et al., Immunity to B16 melanoma in mice immunized with IL 2 secreting allogeneic mouse fibroblasts expressing melanoma associated antigens, Int. J. Cancer, 51: 283 289 (1992). *
Kim. T.S. et al., Immunity to B16 melanoma in mice immunized with IL-2-secreting allogeneic mouse fibroblasts expressing melanoma associated antigens, Int. J. Cancer, 51: 283-289 (1992).
Marshall, Science, 269:1050 1055, 1995. *
Marshall, Science, 269:1050-1055, 1995.
Miller et al., FASEB J., 9:190 199, 1995. *
Miller et al., FASEB J., 9:190-199, 1995.
Nih "Report and Recommendations . . . ", Dec. 7, 1995, 1-40.
Nih Report and Recommendations . . . , Dec. 7, 1995, 1 40. *
Ostrand Rosenberg et al, Tumor Specific Immunity . . . , Int. J. Cancer. Supp. 6, 61 68 (1991. *
Ostrand Rosenberg, S. et al., Tumor specific immunity can be enhanced by transfection of the tumor cells with syngeneic MHC class II genes or allogeneic MHC class I genes, Int. J. Cancer, 6(suppl.): 61 68 (1991). *
Ostrand-Rosenberg et al, Tumor Specific Immunity . . . , Int. J. Cancer. Supp. 6, 61-68 (1991.
Ostrand-Rosenberg, S. et al., Tumor-specific immunity can be enhanced by transfection of the tumor cells with syngeneic MHC class II genes or allogeneic MHC class I genes, Int. J. Cancer, 6(suppl.): 61-68 (1991).
Pardoll, D.M., Cancer vaccines, Immunol. Today, 14(6): 310 316 (1993). *
Pardoll, D.M., Cancer vaccines, Immunol. Today, 14(6): 310-316 (1993).
Pardoll, D.M., New strategies for active immunotherapy with genetically engineered tumor cells, Curr. Opin. Immunol., 4: 619 623 (1992). *
Pardoll, D.M., New strategies for active immunotherapy with genetically engineered tumor cells, Curr. Opin. Immunol., 4: 619-623 (1992).
Porgador, A. et al., Anti metastatic vaccination of tumor bearing mice with IL 2 gene inserted tumor cells, Int. J. Cancer, 53: 471 477 (1993). *
Porgador, A. et al., Antimetastatic Vaccination of Tumor Bearing Mice with Two Types of IFN y Gene Inserted Tumor Cells, J. Immunol., 150: 1458 1470 (1993). *
Porgador, A. et al., Anti-metastatic vaccination of tumor-bearing mice with IL-2-gene-inserted tumor cells, Int. J. Cancer, 53: 471-477 (1993).
Porgador, A. et al., Antimetastatic Vaccination of Tumor-Bearing Mice with Two Types of IFN-y Gene-Inserted Tumor Cells, J. Immunol., 150: 1458-1470 (1993).
Porgador, A. et al., Interleukin 6 Gene Transfection into Lewis Lung Carcinoma Tumor Cells Suppresses the Malignant Phenotype and Confers Immunotherapeutic Competence against Parental Metastatic Cells, Cancer Res., 52: 3679 3686 (1992). *
Porgador, A. et al., Interleukin 6 Gene Transfection into Lewis Lung Carcinoma Tumor Cells Suppresses the Malignant Phenotype and Confers Immunotherapeutic Competence against Parental Metastatic Cells, Cancer Res., 52: 3679-3686 (1992).
Rosenberg, S.A., The immunotherapy and gene therapy of cancer, J. Clin. Oncol., 10: 180 199 (1992). *
Rosenberg, S.A., The immunotherapy and gene therapy of cancer, J. Clin. Oncol., 10: 180-199 (1992).
Russell, S.J. et al., Decreased tumorigenicity of a transplantable sarcoma following transfer and expression of an IL 2 cDNA, Int. J. Cancer, 47: 244 251 (1991). *
Russell, S.J. et al., Decreased tumorigenicity of a transplantable sarcoma following transfer and expression of an IL-2 cDNA, Int. J. Cancer, 47: 244-251 (1991).
Weber, J.S. et al., Modulation of Murine Tumor Major Histocompatibility Antigens by Cytokines in Vivo and in vitro, Cancer Res., 48: 5818 5824 (1988). *
Weber, J.S. et al., Modulation of Murine Tumor Major Histocompatibility Antigens by Cytokines in Vivo and in vitro, Cancer Res., 48: 5818-5824 (1988).
Yamada, G. et al., Retroviral expression of the human IL 2 gene in a murine T cell line results in cell growth autonomy and tumorigenicity, EMBO J., 6: 2705 2709 (1987). *
Yamada, G. et al., Retroviral expression of the human IL-2 gene in a murine T cell line results in cell growth autonomy and tumorigenicity, EMBO J., 6: 2705-2709 (1987).
Zoller, M. et al., Interferon Gamma Treatment of B16 Melanoma Cells: Opposing Effects for Non Adaptive and Adaptive Immune Defense and its Reflection by Metastatic Spread, Int. J. Cancer, 41: 256 266 (1988). *
Zoller, M. et al., Interferon-Gamma Treatment of B16 Melanoma Cells: Opposing Effects for Non-Adaptive and Adaptive Immune Defense and its Reflection by Metastatic Spread, Int. J. Cancer, 41: 256-266 (1988).

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030170656A1 (en) * 1995-10-16 2003-09-11 Chiron Corporation Method of screening for factors that modulate gene expression
US7264820B2 (en) 1996-07-25 2007-09-04 The Regents Of The University Of California Cancer immunotherapy using autologous tumor cells combined with cells expressing a membrane cytokline
US6277368B1 (en) 1996-07-25 2001-08-21 The Regents Of The University Of California Cancer immunotherapy using autologous tumor cells combined with cells expressing a membrane cytokine
US7364726B2 (en) 1996-07-25 2008-04-29 The Regents Of The University Of California Pharmaceutical composition for cancer treatment containing cells that express a membrane cytokine
US20080057029A1 (en) * 1996-07-25 2008-03-06 Hiserodt John C Cancer immunotherapy using autologous tumor cells combined with cells expressing a membrane cytokine
US7670611B2 (en) 1997-01-31 2010-03-02 The Board Of Trustees Of The University Of Illinois Cancer immunotherapy with semi-allogeneic cells
US20080305131A1 (en) * 1997-01-31 2008-12-11 The Board Of Trustees Of The University Of Illinois Cancer Immunotherapy with Semi-Allogeneic Cells
US20030108517A1 (en) * 1997-07-29 2003-06-12 Immune Response Corporation Membrane-bound cytokine compositions and methods of modulating an immune response using same
US5891432A (en) * 1997-07-29 1999-04-06 The Immune Response Corporation Membrane-bound cytokine compositions comprising GM=CSF and methods of modulating an immune response using same
US6482407B2 (en) 1997-07-29 2002-11-19 The Immune Response Corporation Membrane-bound cytokine compositions comprising GM-CSF or an active fragment thereof and methods of modulating and an immune response using the same
WO1999006544A1 (fr) * 1997-07-29 1999-02-11 The Immune Response Corporation Compositions a base de cytokine membranaire et procedes de modulation d'une reponse immune faisant appel a ces compositions
US20050069960A1 (en) * 1998-03-20 2005-03-31 Nicolette Charles A. Novel complementing receptor-ligand pairs and adoptive immunotherapy using the same
WO1999047178A1 (fr) * 1998-03-20 1999-09-23 Genzyme Corporation Nouvelles paires complementaires de recepteurs /ligands et immunotherapie adoptive les utilisant
US20060009393A1 (en) * 1999-10-02 2006-01-12 The Government of the U.S.A as represented by the Secretary of the Dept. of Health & Human Services Immunogenic epitopes for fibroblast growth factors 5 (FGF-5)
EP1964573A2 (fr) 1999-10-22 2008-09-03 Aventis Pasteur Limited Procédé d'induction et/ou amélioration d'une réponse immune vers des antigènes de tumeurs
EP1871166A2 (fr) * 2005-03-29 2008-01-02 The Board Of Trustees Of The University Of Illinois Vaccins contre le cancer et methodes therapeutiques
EP1871166A4 (fr) * 2005-03-29 2008-11-12 Univ Illinois Vaccins contre le cancer et methodes therapeutiques
US20090214494A1 (en) * 2005-03-29 2009-08-27 The Board Of Trustees Of The University Of Illinoi Cancer Vaccines and Therapeutic Methods
US9186418B2 (en) 2005-03-29 2015-11-17 The Board Of Trustees Of The University Of Illinois Method of identifying tumor associated antigens
US20110014241A1 (en) * 2008-03-14 2011-01-20 The Board of Trustees of the Unversity Illinois Therapeutic Cancer Antigens
US11471453B2 (en) * 2013-11-26 2022-10-18 Technion Research & Development Foundation Limited Neuronal modulation

Also Published As

Publication number Publication date
WO1995031107A1 (fr) 1995-11-23

Similar Documents

Publication Publication Date Title
US5759535A (en) Immunotherapeutic strategies for the treatment of cancer
Gansbacher et al. Interleukin 2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity.
Cao et al. Lymphotactin gene-modified bone marrow dendritic cells act as more potent adjuvants for peptide delivery to induce specific antitumor immunity
ES2334407T3 (es) Composiciones y metodos para inmunidad mejorada de celulas neoplasicas in vivo.
McBride et al. Genetic modification of a murine fibrosarcoma to produce interleukin 7 stimulates host cell infiltration and tumor immunity
US5470730A (en) Method for producing TH -independent cytotoxic T lymphocytes
JP4094053B2 (ja) 免疫または炎症応答の調節による抗がん遺伝子療法
US20050053579A1 (en) Novel synthetic chimeric fusion transgene with immuno-therapeutic uses
Kim et al. Interleukin-2-secreting mouse fibroblasts transfected with genomic DNA from murine melanoma cells prolong the survival of mice with melanoma
US9186418B2 (en) Method of identifying tumor associated antigens
Porgador et al. Combined vaccination with major histocompatibility class I and interleukin 2 gene-transduced melanoma cells synergizes the cure of postsurgical established lung metastases
Hurwitz et al. Enhancement of the anti‐tumor immune response using a combination of interferon‐γ and B7 expression in an experimental mammary carcinoma
Kim et al. Immunity to B16 melanoma in mice immunized with IL‐2‐secreting allogeneic mouse fibroblasts expressing melanoma‐associated antigens
Sumimoto et al. GM‐CSF and B7‐1 (CD80) co‐stimulatory signals co‐operate in the induction of effective anti‐tumor immunity in syngeneic mice
AU651397B2 (en) Method for producing TH-independent cytotoxic T lymphocytes
Kim et al. Immunization with interleukin‐2‐secreting allogeneic mouse fibroblasts expressing melanoma‐associated antigens prolongs the survival of mice with melanoma
EP0538952B1 (fr) Vaccin anti-tumoral comprenant des cellules transformées pour l'expression de l'interleukine-6
Moret-Tatay et al. Complete tumor prevention by engineered tumor cell vaccines employing nonviral vectors
Blankenstein Increasing tumour immunogenicity by genetic modification
Pizzoferrato et al. Enhanced immunogenicity of B cell lymphoma genetically engineered to express both B7-1 and interleukin-12
Qian et al. Efficient tumor regression induced by genetically engineered tumor cells secreting interleukin-2 and membrane-expressing allogeneic MHC class I antigen
Kim et al. Immunization of mice with allogeneic fibroblasts genetically modified for interleukin-2-secretion and expression of melanoma-associated antigens stimulate predetermined classes of anti-melanoma effector cells
Santin et al. Development and characterization of an IL-4-secreting human ovarian carcinoma cell line
Tahara et al. Gene Therapy for Adult Cancers: Advance in Immunologic Approaches Using Cytokines
Carr-Brendel et al. Immunity to breast cancer in mice immunized with X-irradiated breast cancer cells modified to secrete IL-12

Legal Events

Date Code Title Description
AS Assignment

Owner name: NATIONAL INSTITUTES OF HEALTH, THE EXTRAMURAL INVE

Free format text: CONFIRMATORY LICENSE;ASSIGNOR:ILLINOIS, UNIVERSITY OF;REEL/FRAME:008091/0310

Effective date: 19960417

AS Assignment

Owner name: RESEARCH CORPORATION TECHNOLOGIES, INC., ARIZONA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:COHEN, EDWARD P.;REEL/FRAME:008803/0460

Effective date: 19970605

STCF Information on status: patent grant

Free format text: PATENTED CASE

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

Free format text: PAYER NUMBER DE-ASSIGNED (ORIGINAL EVENT CODE: RMPN); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

CC Certificate of correction
FPAY Fee payment

Year of fee payment: 4

AS Assignment

Owner name: UNIVERSITY OF ILLINOIS AT CHICAGO, ILLINOIS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:RESEARCH CORPORATION TECHNOLOGIES, INC.;REEL/FRAME:016237/0657

Effective date: 20030319

FPAY Fee payment

Year of fee payment: 8

FPAY Fee payment

Year of fee payment: 12